A multifaceted study for the development of new antitumor nucleosides is proposed. It entails the synthesis of new nucleoside analogs, based upon structure-activity relationships recognized in previous work, followed by the evaluation of compounds for their antitumor effect. If active, the analogs will undergo studies on their modes of action including determinations of kinetics of their interaction with specific target enzymes. Particular attention will be paid to the regulatory effects which the analogs may exert on the cell metabolism. Added to this biochemical evaluation are studies on the pharmacological disposition of the compounds in the animal. An evaluation will also be undertaken of the biological and biochemical effects which nucleoside analogs exert in combination with natural metabolites and with other antimetabolites selected on the basis of their recognized site of action, and new concepts such as metabolic conditioning will be explored. The data thus obtained will be used to establish correlations between the change in chemical structure and the nature of the biological and biochemical activity resulting from it.